Beginning in the fall of 1996, there was evidence of increasing activity of Pfiesteria and Pfiesteria-like dinoflagellates in estuarine areas on the easter shore of the Chesapeake Bay, as manifested by characteristic "punched out" lesions and erratic behavior in fish. Persons exposed to affected waterways reported problems with confusion, "forgetfulness," headaches, and skin and respiratory irritation; on neuropsychologic evaluation, exposed persons had significant impairments in learning, with 75% of persons with a high level of exposure to affected waterways having scores on learning measures which were below the 2nd percentile for age- and educationally-stratified population norms. Based on these observations, we hypothesize that toxins produced by Pfiesteria-like dinoflagellates present in Maryland waters cause specific impairments in human learning and memory. We propose to further explore this hypothesis (and related questions about Pfiesteria) in a comprehensive interwoven program incorporating 6 projects and three supporting core activities. Projects include: 1) Neuropsychologic studies, focusing on defining the nature and extent of learning and memory impairments in affected persons; 2) Molecular genetic studies, directed toward genetic identification and characterization of the Pfiesteria species present in Maryland; 3) Studies of mechanisms underlying toxin expression by the dinoflagellate; 4) Comparative medicine studies, exploring the responses of fish to specific toxins, and the relationship of these response to observations in humans; 5) Neurotoxicologic studies, looking at the responses to toxin preparations in tissue culture and animals models, and evaluating possible mechanisms underlying these responses; and 6) Epidemiologic studies, to link human health effects with specific environmental exposures. Projects will be supported by administrative; clinical; and dinoflagellate culture, bioassay, and toxin production core activities; the latter core will include BSL3 laboratory facilities. Pfiesteria, with its propensity for killing fish and its human health effects, has generated great public concern and had a profound economic impact on affected area. Data from the proposed studies are essential if we are to understand the real risks associated with this microorganisms and develop rational interventions to protect public health.